The development of biocompatible nanoparticles for in vivo molecular imaging and targeted therapy is an area of considerable current interest across a number of science, engineering and biomedical disciplines. The basic rationale is that nanometer-sized particles have functional and structural properties that are not available from either discrete molecules or bulk materials. When conjugated with biomolecular targeting ligands such as monoclonal antibodies, peptides or small molecules, these nanoparticles can be used to target malignant tumors with high specificity and affinity. In the ‘mesoscopic’ size range of 10- to 100-nm diameter, nanoparticles also have large surface areas for conjugating to multiple diagnostic (e.g., optical, radioisotopic or magnetic) and therapeutic (e.g., anticancer) agents. Recent advances have led to the development of biodegradable nanostructures for drug delivery, iron oxide nanocrystals for magnetic resonance imaging, quantum dots for multiplexed molecular diagnosis and in vivo imaging, and nanoscale carriers for short interfering RNA (siRNA) delivery.
Colloidal gold has been safely used to treat rheumatoid arthritis for half a century, and recent work indicates the pegylated gold nanoparticles (colloidal gold coated with a protective layer of polyethylene glycol or PEG) exhibit excellent in vivo biodistribution and pharmacokinetic properties upon systemic injection. In contrast to cadmium-containing quantum dots and other toxic or immunogenic nanoparticles, gold colloids have little or no long-term toxicity or other adverse effects in vivo. The discovery of single-molecule and single-nanoparticle surface-enhanced Raman scattering (SERS) has attracted considerable interest, both for fundamental studies of enhancement mechanisms and for potential applications in ultrasensitive optical detection and spectroscopy. A number of researchers have shown that the enhancement factors are as large as 1014-1015, leading to Raman scattering cross sections that are comparable to or even larger than those of fluorescent organic dyes. This enormous enhancement allows spectroscopic detection and identification of single molecules located on the surface of single nanoparticles or at the junction of two particles at room temperature. Progress has been made concerning both the structural and mechanistic aspects of single-molecule SERS, but it is still unclear how this large enhancement effect might be exploited for applications in analytical chemistry, molecular biology, or medical diagnostics. One major problem is the intrinsic interfacial nature of SERS, which requires the molecules to adsorb on roughened metal surfaces. For biological molecules such as peptides, proteins, and nucleic acids, surface-enhanced Raman data are especially difficult to obtain, hard to interpret, and nearly impossible to reproduce.